Renal cell carcinoma (RCC) is the most common malignancy of the kidney, accounting for more than 58,000 new diagnoses of cancer and 13,000 cancer deaths in the United States during 2010. The central theme of this R21 (PAR 08-147) is to refine the current use of Positron Emission Tomography of 124I-cG250 (ImmunoPET) in RCC as a pharmacodynamic and predictive biomarker during sunitinib targeted drug therapy. This is a resubmission of our prior R21 scored at the 15th percentile. We have addressed the reviewer's critique, based primarily on newly available literature and data from the Phase III Wilex trial. We propose a single center, open-label, investigator-initiated, pilot study of 124I-cG250 imaging in 25 patients with advanced or metastatic clear cell RCC who are scheduled to receive treatment with sunitinib for clinical indications. The 124I-cG250 imaging test x 3 at baseline, during treatment and in follow-up, will be assessed for its ability to predict response i comparison to bone scan, high resolution body CT scan of the chest, abdomen, and pelvis, RECIST version 1.1, time to progression and survival. The trial will be performed in collaboration with Dr. Robert Motzer, Genitourinary medical oncologist, who has pioneered improved targeted drug therapies for RCC. Our core hypothesis is that at baseline, detection of CAIX antigen expression in clear cell renal cancer, based on 124I- cG250 ImmunoPET, will provide improved single test staging in comparison to standard CT and bone scan;Also, ImmunoPET measured changes in 124I-cG250 uptake will provide earlier and more accurate assessment of treatment response in advanced metastatic RCC, in comparison to RECIST 1.1. This R21 grew out of diagnostic and therapeutic studies with radiolabeled G250, in which we and others determined that in vivo targeting in mice and patients bearing clear cell renal cancer resulted in exceptional target to background ratios and % injected dose per gram. Based on this knowledge, we performed a Phase I study with 124I-cG250 for detection of clear-cell renal cancer, hoping to exploit the combination of an exceptional targeting antibody, and the sensitivity and quantitative power of PET imaging, for improved diagnosis in man. The clinical rationale was to characterize non-invasively, the histology of a renal mass and therefore avoid unnecessary renal surgery that could potentially damage kidneys that are often already clinically compromised. The phase I study found the PET imaging approach to be highly effective for the non-invasive diagnosis of clear cell renal cancer (Divgi et al: Lancet Oncol 2007;8:304-10). Subsequently, Wilex Inc, in partnership with IBA US, licensed the approach and has now completed a Phase III pivotal trial with 124I-cG250. Study results are now with the FDA for review. As far as we are aware, this is the first positron labeled antibody that has been manufactured under GMP conditions and submitted for a diagnostic NDA from the FDA. The current proposal is a logical extension of these prior studies and, if successful, will improve staging and monitoring of systemic treatment response in advanced renal cell carcinoma. PUBLIC HEALTH RELEVANCE: In 2010, 13,000 US patients will die of advanced Renal Cancer. Recently, promising new drugs that block growth signals responsible for proliferation (sunitinib) have been developed, but these agents are only effective in 50% of the patients, and those who do not respond may experience unpleasant side-effects. Positron Emission Tomography based molecular imaging using 124I-cG250 ImmunoPET will help select individual patients who will respond to these drugs and improve individual patient management.